Navigating therapeutic challenges: Voriconazole pharmacokinetics and CYP2C19 genetic polymorphism-A case report and literature review

Abstract

Scedosporium apiospermum is an opportunistic fungal pathogen that causes various infections in immunocompromised patients. Voriconazole is the first-line treatment; however, its clinical use is often challenging due to complex pharmacokinetics and significant interpatient variability, primarily driven by polymorphisms in the CYP450 (CYP2C19) enzymes. These genetic variations affect drug metabolism, resulting in suboptimal drug levels or increased toxicity. We present a case of atraumatic localized Scedosporium apiospermum mycetoma on the back of a patient with a renal transplant. The patient underwent surgical excision and was initiated on voriconazole with a loading dose of 400 mg (6 mg/kg) every 12 h on day one, followed by 200 mg every 12 h (4 mg/kg twice daily). Despite dose adjustments, voriconazole serum levels remained persistently sub-therapeutic. Pharmacokinetic and pharmacogenetic studies were conducted for further evaluation. Pharmacokinetic analysis revealed a shortened voriconazole half-life. Pharmacogenetic testing identified a CYP2C19 *1/*17 genotype, indicating a rapid metaboliser phenotype. This resulted in accelerated drug metabolism, low serum levels and an increased risk of treatment failure and disease progression. Alternative agents to voriconazole, independent of CYP2C19 (isavuconazole, liposomal amphotericin B or posaconazole) were recommended for current and future therapy. Pharmacogenetic and pharmacokinetic testing may play a role in optimizing antifungal therapy. CYP2C19 polymorphisms significantly affect voriconazole metabolism. Patients that are poor metabolisers have greater drug exposure compared with rapid metabolisers. Genotyping may help guide dosage adjustments, predict potential drug interactions and improve treatment efficacy whilst reducing adverse effects. The integration of pharmacogenomic testing, along with therapeutic drug monitoring (TDM), can enhance individualized therapy for both antifungal treatment and prophylaxis in complex clinical scenarios.